The central objectives of this research proposal are to characterize and identify the antigen-antibody systems lupus erythematosus (SLE) and other connective tissue diseases and to investigate their pathogenetic role in tissue injury. A key approach is the use of human disease sera containing monospecific antinuclear antibodies as reagents to identify and isolate nuclear macromolecules with antigenic properties. These nuclear antigens comprise DNA, deoxyribonucleoprotein, Sm antigen (an acidic nuclear macromolecule devoid of DNA or RNA), nuclear ribonucleoprotein, and a nucleolar RNA component. Some of the nuclear antigens have been only partially characterized and with the use of spontaneously occurring antibodies in human disease, attempts will be continued to isolate and characterize them further. Purified antibodies, labelled with radiosotopes or with fluorescein, will be used to determine if immune complexes involving these antigens are involved in tissue injury. Radioimmunoassay methods already available for DNA and deoxyribonucleoprotein will be used to monitor relationship of disease activity with circulating antibody or antigen. Finally, in order to investigate the causes of breakdown of tolerance in SLE, levels of intra and extracellular nucleases will be studied to determine if nuclease activity might be depressed in SLE. The presence of aberrant immunity in SLE will also be studied by looking for cell membrane receptors for the nuclear antigens described above.